BIOEQUIVALENCE COMBINATION 776C85/5FU PILL & INDIVIDUAL 776C85 & 5FU PILL

目的：这项I期研究旨在确定联合化疗药物776C85/5-FU的片剂与单独的776C85和5-FU片剂的生物等效性。复合片的优点包括降低患者接受776C85和标准剂量FU的机会，这可能会导致致命的毒性。它使患者更容易服用药物，并确保患者在没有776C85的情况下不口服5-FU。在临床前和早期临床研究中，776C85显著提高了口服5-FU的生物利用度和半衰期，降低了口服5-FU的药代动力学变异性。在啮齿动物肿瘤模型中，5-FU的抗肿瘤作用增强，治疗指数提高6倍。方法：这是一项在36名患者中进行的随机、开放标签的3向交叉研究，将单独的5-FU和776C85片剂与775C85和5-FU片剂的每种剂量组合进行比较。每个受试者被随机分配到六个治疗序列中的一个，并在每个研究期间接受三个治疗中的一个，并在研究期间接受所有三个治疗。每个周期包括两天的剂量和五天的洗涤。776C85(20 Mg)单剂给药，每日2次，第1天给药，第2天晚上给药。所有患者在第2天早晨分别接受2.0 mg的5-FU和20 mg的776C85。在每次5-FU治疗后采集系列血样，测定血浆中5-FU、776C85和尿嘧啶的浓度。结果：本研究于1998年4月20日结束。这项研究达到了其应计目标。共有11名Duke患者入选。所有患者都完成了这项I期研究，并继续在另一项开放标签研究下接受药物治疗。没有可报告的不良事件。总体而言，患者的生活质量似乎有所改善，症状减少，病情稳定。未来计划：根据这项试验的结果，该组合片剂将用于进一步的研究。

Purpose: This phase I study was designed to determine the bioequivalence of a tablet combining the chemotherapeutic agent 776C85/5-FU to the individual 776C85 and 5-FU tablets. Advantages of a combination tablet include a reduction in the chance that a patient would receive 776C85 and a standard dose of FU, which could result in a fatal toxicity. It makes it easier for patients to take the medication, and it ensures that patients do not take oral 5-FU without 776C85. In preclinical and early clinical studies, 776C85 significantly increased the bioavailability and half-life of oral 5-FU, and reduced the pharmacokinetic variability of oral 5-FU. It also increased the antitumor efficacy of 5-FU and increased the therapeutic index of 5-FU up to six-fold in rodent tumor models. Methods: This was a randomized, open-label 3-way crossover study in 36 patients comparing individual 5-FU and 776C85 tablets to each strength of the combination of 775C85 and 5-FU tablet. Each subject was randomly assigned to one of six treatment sequences and received one of three treatments during each study period and all three treatments during the study. Each period consisted of two days of dosing and a five-day washout. 776C85 (20 mg) was administered as a single agent twice daily on day 1 and as a single evening dose on day 2 of each period. All patients received a 2.0 mg dose of 5-FU and a 20 mg dose of 776C85 on the morning of day 2. Serial blood samples were collected following each dose of 5-FU to measure plasma 5-FU, 776C85, and uracil concentrations. Results: This study was closed to accrual on 4/20/98. The study met its accrual goal. A total of 11 Duke patients were enrolled. All of the patients completed this phase I study and continued to receive drug under a separate open-label study. There were no reportable adverse events. Overall, patients appeared to have improvement in their quality of life with decreased symptoms and stabilization of disease. Future plans: Based on the results of this trial, the combination tablet will be used in further studies.